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By Stephen D. Herman, M.D., D.A.B.R. and James Herman B.Sc.

INTRODUCTION

A new patented medicinal agent designated "TX" was developed in response to the increasingly urgent need to deal with worldwide threat of viral epidemic as well as the increasing occurrence of antibiotic resistant organisms throughout the world. "TX" has been a major breakthrough in therapeutic medicine and its broad efficacy brings into question many long held misconceptions pervading the medical and scientific communities. The following paper will overview the scientific basis underlying "TX", it's characteristics and some therapeutic results. These will be discussed in relation to their implications for the revised concept of the nature of human disease and more rational approach to medical therapy.

The most broadly successful therapy for human disease is provided by our own immune system. This includes all infectious, neoplastic and autoimmune disease. An intact and functioning immune system maintains a disease free state while a suppressed or dysfunctional immune system leaves us susceptible to a wide spectrum of maladies almost without restriction. In view of the fact that the primary functioning module of the immune system, the white blood cell, is
extremely limited in the molecular structures it can produce the question must be raised why the perception persists that each distinct medical insult must be compartmentalized as the chapters in a medical text book. This then justifies the notion that each disease process will require a unique or distinctive medical compound for it's treatment. Logic and the immune system clearly doesn't support this point of view and indeed suggests that exactly the opposite is true.
That is most disease processes are more similar than we thought and that rational approaches to therapy will demonstrate a broader spectrum of effectiveness than has been seen heretofore. These are to be found within the common denominators created by the immune system itself rather than a random search for diverse chemical substances unrelated to human evolution.

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THE RESPIRATORY BURST

Phagocytes employ as antimicrobial agents a number of compounds generated by partial reduction of oxygen (O2). O2 is initially reduced to superoxide (O2) by a membrane associated flavoprotein. This process occurs in a respiratoryburst via glucose oxidation in a hexose monophosphate shunt. Oxidized NADPH participates as follows:

(O2 + NADPH yields 2O2 + NADP + H) subsequently by dismutation
(superoxide dismutase) 2O2 + 2H2 yields O2 + H2O2. Present theory suggests that microbial action by phagocytes is mediated by myeloperoxidase which catalyzes the conversion of H2O2 and Cl to hypochlorous acid (HOCl). In support of the effectiveness of this mechanism it is interesting to note that 2x107 M of HOCL generated by 10x6 neutrophils will destroy 15x10x7 Ecoli in milliseconds. In short, neutrophils purposely generate large quantities of reactive oxidants for microbial purposes. Interestingly, HOCL is the sole active ingredient in
Bleach. HOCL quickly reacts with primary or secondary amines to form an additional family of microbicidal agents called chloramines.

The term "respiratory Burst" refers to a coordinated series of metabolic events that take place when phagocytes are exposed to appropriate stimuli. This group of events underlies all oxygen-dependent killing by phagocytes.

The first of these events to be discovered was a sharp increase in oxygen uptake occurs upon stimulation of the phagocyte. Oxygen consumption, by resting phagocytes varies widely, depending on cell type-neutrophils, for example, consume little oxygen even in oxygen-rich environments, whereas alveolar macrophages rely heavily on oxygen-consuming (mitochondrial) reactions for energy production. All, however, respond to appropriate stimuli with an increase

in oxygen uptake. It was originally thought that the purpose of this rise in oxygen consumption was to provide energy for phagocytosis. Sbarra and Karnovsky showed that phagocytosis occurred under nitrogen as well as under inhibitors of mitochondrial respiration. Both these findings are contrary to the results expected if the augmentation in oxygen uptake were solely to provide ATP as a source of energy for phagocytosis.

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Though the study of Sbarra and Karnovsky showed that the oxygen consumed in the respiratory burst was not used for energy production, it left unexplained the reason for the increase in oxygen uptake. An explanation was soon provided by Lyer, Islam and Quastel. These workers showed that at least part of the oxygen consumed in the respiratory burst was converted to hydrogen peroxide (H2O2), which they detected in a medium surrounding the stimulated phagocyte.

They proposed that this H2O2 was used by the phagocyte as a bacterial agent, and were the first to draw a connection between the respiratory burst and the microbial mechanisms of phagocytes.

Stimulation of the phagocyte was also found to cause an increase in glucose oxidation via the hexose monophosphate shunt. The hexose monophosphate shunt is a metabolic pathway in which glucose is oxidized to carbon dyoxide as a five-carbon sugar, with NADP serving as electron acceptor. In the neutroplex, glucose oxidation by this pathway is limited by the rate at which NADP becomes available through the oxidation of NADHP. Shunt activation therefore meas that the oxidation of NADHP to NADP increased during the respiratory burst.

The most recent event of the respiratory burst discovered is the production of superoxide (O2). This compound, formed by the one-electron reduction of oxygen, has attracted much attention among biologists interested in oxygen metabolism since the discovery of superoxide dismutase, the enzyme that catalyzes the destruction of O2 by the reaction:

2O2 + 2H + —> O2 + NADP + Hoxidase

In turn, two molecules of O2 interact spontaneously (dismutation reaction) to generate one molecule of H2O2.

2O2 + 2H —> H2O2 + O2

Both O2 and H2O2 can react with a number of important biologic substrates, but the rate at which two molecules of superoxide interact at physiologic Ph to form H2O2 is rapid. Thus, under most conditions the preferred substrate for one O2 molecule is a second O2 molecule, and few other substances can compete with the rapid spontaneous dismutation reaction. Second, although H2O2 is a stable oxidant that can exert a number of damaging effects, neutrophils themselves consume the bulk of this metabolite and only a small portion of the
generated H2O2 can actually be detected in the extracellular pool. Other oxidizing agents thought to participate in these systems are O2, hydroxyl radical and singlet oxygen.